Sydnone imine compounds

ABSTRACT

Sydnone imines of general formula:   wherein Z is alkoxy- or alkylenedioxy phenyl, phenoxy, benzhydryl, benzodioxane or a heterocyclic radical, A is a single bond or methylenic chain, n is 0 or 2, and R is a hydrogen atom or an acyl radical. These compounds possess antihypertensive and antianginous properties.

United States Patent 1191 Regnier et al.

I Aug. 5, 1975 SYDNONE IMINE COMPOUNDS [75] Inventors: Gilbert Regnier,Chatenay-Malabry;

Roger Canevari, Villebon sur Yvette; Michel Laubie, Vaucresson, all ofFrance [73] Assignee: Science Union et Cie., Societe Francaise deRecherche Medicale, Suresnes, France [22] Filed: Aug. 2, 1972 [21] Appl.No.: 277,213

[30] Foreign Application Priority Data Aug. 26, 1971 United Kingdom40037/71 52 us. c1..... 260/2564 N; 260/2401; 260/2409; 260/2495;260/2564 R; 260/2564 c;

260/268 BC; 260/268 PH; 260/268 H;

511 lm. c1 C07d 51/42 158 Field Of Search 260/2564 N, 256.4 c, 256.4 R

[56] References Cited UNITED STATES PATENTS 3312.690 4/1967 Musuda etal. 260/239 OTHER PUBLICATIONS Morrison et al., Organic Chemistry, Allyn& Ba-

con, Inc., Boston, (l959),page 367.

Smith, P.,Open-Chain Nitrogen Compounds, Vol. I, W. A. Benjamin, Inc.,New York,l965,page 307.

Primary E.\'aminerDonald G. Daus Assistant E.\'aminerRaymond V. RushAttorney, Agent, or Firm-Omri M. Behr [57] ABSTRACT Sydnone imines ofgeneral formula:

7 Claims, No Drawings SYDNONE IMINE COMPOUNDS R CO The present inventionprovides a sydnone imine dewherein R- re resents: rivative of thegeneral formula I: 2 p

a. a hydrogen atom b. a lower aliphatic radical containing from 1 to 6carbon atoms in a linear or branched chain, which Z-A-N N(CH ),.N maycontain, a carboxylic or a hydroxyl group,

II t N C: c. an aryl, an aralkyl, an arylalkenyl or an aryloxyalkylradical wherein the aryl moieties may be substituted by one or more,preferably one, two or three,

(I) I halogen atoms, for example chlorine and/or fluorine atoms, alkylor alkoxy radicals containing from wherein; 1 to carbon atoms or by oneor two methylenedi- Z represents: oxy or ethylenedioxy radicals,

a. a mono-or poly-alkoxy phenyl radical wherein Py y py y alkyl radicalwherein the alkoxy moiety has from 1 to 4 carbon atoms the alkyl moietyhas from 1 t0 5 Carbon atoms,

or a mono or di alkylenedioxy phenyl radical e. an amino radical of thegeneral formula wherein the alkylenedioxy moiety has from 1 to 2 carbonatoms; b. a phenoxy radical which may be substituted by R 3 one or morehalogen atoms or alkyl or alkoxy radicals containing from 1 to 4 atoms;i c. a benzhydryl radical optionally substituted on the phenyl rings byone or more halogen atoms. 1, a di al f th general f ula; wherein Rrepresents a hydrogen atom, an alkyl or alkenyl radical containing from1 to 5 carbon atoms and R represents an alkyl or alkenyl radicalcontaining O X from 1 to 5 carbon atoms or a phenyl radical.

0 H2 A compound of the general formula I wherein R is a g hydrogen atomis prepared by a process analogous to that described in the US. Pat. No.3,312,690, accordwherein X represents a hydrogen atom, a halogen ing tothe following equations:

CH O

fi a) Z-A-N N(CH ),,NH Z-A-N N(CH ),,NHCH CN J HCN or ClCH CN (n (lll)NaNO atom or an alkyl or alkoxy radical containing from 1 to The step(a) may be carried out, in the case where n 4 carbon atoms; or is 0, forexample, by treating a mineral acid addition e. a heterocyclic radicalof the general formula salt of an amine of the general formula ll with aslight excess of sodium cyanide, in the presence of an aqueousformaldehyde solution, at a temperature within the ,Y' range of from 0to25C. In the case where: n is 2,, his Y R more convenient to carry outstep (a) by condensing J N l chloracetonitrile with an excess of theamine ll, which acts as acceptor for the hydrochloric acid formed duringthe reaction, in the presence of a weak polar aprowherei Y and Y, whi hmay b th same differtonic solvent, for example tetrahydroguran ordioxan, ent each represents N or CH and R represents hydroat atemperature Within thfi: range of from 250) gen, a alkyl or alkoxyradical containing from 1 to 4 The step (b) maybe carried out, forexample, by carbon atoms; treating a mineral acid addition salt of anaminonitrile A represents a single bond or a li e or b h d of thegeneral formula III with an excess of an aqueous methylenic radicalcontaining from 1 t 4 carbon sodium nitrite solution at a temperaturewithin the atoms optionally having an ethylenic double bond; range offrom 0 to 25 C. n represents or 2; and The step (c) may be carried outfor example, by R represents a hydrogen atom or an acyl radicaldetreating, at room temperature, a nitrosoaminonitrile of rived from acarboxylic, or a carbamic acid, of the the general formula IV with anexcess of a methanolic general formula hydrochloric acid solution in thecase where n is 0 or with an excess of an aqueous hydrochloric acidsolution in the case where n is 2.

The sydnone imines of the general formula I wherein R represents an acylradical is prepared, by acylating a sydnone imine of the general formula1 wherein R is a hydrogen atom. One of the most satisfactory ways ofcarrying out this process comprises treating a mineral acid additionsalt of a sydnone imine of the general formula 1 wherein R is a hydrogenatom, with a suitable derivative of a desired acid for example, ahalide, an anhydride, a lactone or an iso-cyanate, at a temperaturewithin the range of from Oto 25C, in the presence of a large excess of atertiary organic base, for example pyridine, which acts as acceptor forthe hydrohalic acid or the carboxylic acid formed during the reaction.

The compounds of the present invention are weak bases which may beconverted with acids into acid addition salts, which are also includedwithin the scope of the present invention. As acids used to form thesesalts, there may be especially mentioned, for example, in the mineralseries: hydrochloric, hydrobromic, sulphuric and phosphoric acids and inthe organic series: acetic, propionic, maleic, fumaric, tartaric,citric, oxalic, benzoic, methanesulphonic and isethionic acids.

The compounds of the general formula 1 and acid addition salts thereofmay be purified by crystallisation or chromatographic absorption.

The compounds of the present invention and the physiologically tolerablesalts thereof possess soluable pharmacological and therapeuticproperties, especially hypotensive, vasodilator and antiangionousproperties.

Their toxicity is weak and the LD 50 determined in mice byintraperitoneal route.

The hypotensive activity of the new compounds was studied in normal andhypertonic, anesthetised and non anesthetised dogs. It was observed thatdoses of 0.5 to 5 mg/Kg of these compounds when administeredintravenously or perorally decrease the blood presure by from about tomore than 60 mm Hg. In the same time the decrease of the pulmonarypressure and that of the myocardial oxygen consumption are alsoobserved.

The above described properties and the low toxicity allow the use of thenew compounds in therapy, especially in the treatment of hypertensionand angina pectoris.

The present invention also provides pharmaceutical compositionscontaining a compound of general formula l or a physiologicallytolerable salt thereof in admixture or conjunction with a suitablepharmaceutical carrier, such for example, as distilled water, glucose,lactose, talc, starch, ethycellulose or cocoa butter. The pharmaceuticalforms may be tablets, capsules, suppositories or solutions for oral,rectal or parenteral administration at doses of 5 to 300 mg preferably25 to mg l to 5 times a day.

The present invention also provides a pack comprising a pharmaceuticalpreparation of the invention together with instructions, theinstructions requiring that it be administered orally, rectally orparenterally, 1 to 5 times a day, in the doses of from 5 to 300 mgespecially for the treatment of hypertensions and angina pectoris.

The following Examples illustrate the invention. The melting points weredetermined in a capillary tube, unless otherwise stated.

EXAMPLE I II N C= NH, 2HCI ml of a methanolic solution containing 30% ofdry hydrogen chloride were added to a solution of 15 g (0.060 mole) ofN-[4-( 2-pyrimidinyl)-l-piperaziny11- N-nitroso-aminoacetonitrile, M.P.:97l00C, in 250 ml of methanol. The mixture was allowed to stand at roomtemperature for 6 hours. There was obtained 10.5 g of3-[4-(2-pyrimidinyl)-1-piperaziny1]-1 sydnone imine dihydrochloride(white crystals) melting at 183C with decomposition, which weresuctioned off. (Yield: 54 The N-[4-(2-pyrimidinyl)-1-piperazinyl]-N-nitroso-amino-acetonitrile used as starting material wasprepared by nitrosation, with an excess of sodium nitrite inhydrochloric acid medium, of[4-(2-pyrimidinyl)-1-piperaziny1]-aminoacetonitrile, melting at 8285C,itself prepared, according to the Mannich reaction, starting from anexcess of a formaldehyde solution, sodium cyanide and l-amino-4-(2-pyrimidiny1)-piperazine dihydrochloride melting at 24l-244C.

EXAMPLES 2 To 6 The compounds listed in Table I were prepared by methodsanalogous to the process described in Example 1. This table alsocontains the melting points of the starting materials.

TABLE I General Formula:

ZAN N- N N C=NH Melting Point Melting Point of of the corresthecorresponding Ex, ZA Isolated Form Melting pondingN-nitrosoaminoacetonitrile No. Point amino acetolll) (dec) nitrile (1V)CH- dihydrochloride 151C 1 19 123C 109 l 12C C H (base) (base) TABLE IContinued General Formula:

II t a N C=NH Melting Point Melting Point of of the corresthecorresponding Ex. ZA- Isolated Form Melting pondingN-nitrosoaminoacetonitrile No. Point amino aceto- (lll) (dec) nitrile(IV) 3 O dihydrochloride 192C 82 86C 82 86C N (base) H C 4 xxdihydrochloride 185C Oil 86 90C H 3 C CH 3 5 Q monohydrochloride 172COil 188C (dec) (dihydrochloride OCH3 O 6 Q l dihydrochloride l6l- 130C75C 0 I63C (Kofler base) (Kofler base) EXAMPLE 7 EXAMPLES 8 3-{ 4-(2-pyrimidinyl l -piperazinyl]-ethyl-sydnone imine, trihydrochloride Thecompounds listed in Table II were prepared by methods analogous to theprocess described in Exam- TABLE II General Formula:

N (CH) N H n I Melting Point of the cones Melting point of the Ex. ZAMelting Point ponding N-nitrosocorresponding amino No. aminoacetoacetonitrile (Ill) nitrile (IV) 0 H 3 C c H a 8 H (,0 187C (dec)73C (Kofler) 188 l90C 3 H 3 base trihydrochloride ple 8. This table alsocontains the melting points of the starting materials.

EXAMPLE 9 3-[4-( 2-pyrimidinyl l -piperazinyl]-N-propionylsydnone imine10 g of 3-[4-(2-pyrimidinyl)-l-piperazinyl]-sydnone iminedihydro-chloridc, prepared according to the Example l, were added slowlyto a solution of 63.1 ml of 65 propionic anhydride in 366 ml ofpyridine. Total dissolution was observed 10 minutes after the completionof the addition the mixture was allowed to stand at room 8 pyrimidinyl l-piperazinyl ]-N-propionyl-syclnone imine, white crystals melting atl46-147C. (Yield: 59 7c).

EXAMPLES 10 To 24 The compounds listed in the Table III were prepared bymethods analogous to the process described in Example 13.

TABLE III General Formula:

N C=1-1 Co-R (base) Ex. ZA- R2 Melting Point No.

1 11 -C2H5 175 178C (dec) o 11 "z "2 2 143 145C (dec) 12 C2H5 127 129CH3 C H :BQHE -C2H 87 90C (hydrate) 14 C2H5 159- l6lC 15 @fl c2115 88 c16 CMCH C2 5 134C N O l g --CH CH CH3 132 133 C 18 Q CH -CH. CH 141 C 3(3H3 19 CH;, 122 123 C om CH3 C11 1 o 20 -(I--CH,, 140 141 C 0011 vc11170 172 C OCH3 3 oc11 23 N 1x5 186 C General Formula:

3. 3-[4 (2-pyrimidinyl)-l-piperazinyl] ethylsydnone imine andphysiologically tolerable acid addition salts thereof being compounds ofclaim 1.

4. 3-[4 (2-pyrimidinyl)-l-piperazinyl] N propionyl sydnone imine andphysiologically tolerable acid addition salts thereof being compounds ofclaim 1.

5. 3-[4 (Z-pyrimidinyl) l piperazinyl] N butyryl sydnone imine andphysiologically tolerable acid addition salts thereof being compounds ofclaim 1.

6. 3-[4 (Z-pyrimidinyl) l piperazinyl] N pivaloyl sydnone imine andphysiologically tolerable acid addition salts thereof being compounds ofclaim 1.

7. 3-[4 (Z-pyrimidinyl) l piperazinyl] N (3,4,5, trimethoxybenzoyl)sydnone imine and physiologically tolerable acid addition salts thereofbeing compounds of claim 1.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A. 3-(4 -(2-PYRIMIDINYL)-1-PIPERAZINYL) - SYDNONE IMINE,3-)-2-PYRIMIDINYL-1-PIPERAZINYL) - ETHYL - SYDNONE IMINE,3-(4-(2-PYRIMIDINYL)-1-PIPERAZNYL)-N-PROPONYL SYDNONE IMINE, 3-(4-(PYRIMIDINYL)-1-PIPERAZINYL) -NBUTYRYL SYDNONE IMINE, 3-(4-(2-PYRIMIDINYL) - 1 PIPERAZINYL)- N - PIVALOYL SYDNONE IMINE, 3 -(4-(2PYRIMIDINYL)-1-PIPERAZINYL)-N-(3,4,5,-TRIMETHOHOXYBENZOYL) SYDNONEIMINE, AND B. PHYSIOLOGICALLY TOLERABLE ACID ADDITION SALTS THEREOF. 2.3-(4 - (2-pyrimidinyl)-1-piperazinyl) - sydnone imine andphysiologically tolerable acid addition salts thereof being compounds ofclaim
 1. 3. 3-(4 - (2-pyrimidinyl)-1-piperazinyl) - ethyl-sydnone imineand physiologically tolerable acid addition salts thereof beingcompounds of claim
 1. 4. 3-(4 - (2-pyrimidinyl)-1-piperazinyl) - N -propionyl sydnone imine and physiologically tolerable acid additionsalts thereof being compounds of claim
 1. 5. 3-(4 - (2-pyrimidinyl) -1 - piperazinyl) - N - butyryl sydnone imine and physiologicallytolerable acid addition salts thereof being compounds of claim
 1. 6.3-(4 - (2-pyrimidinyl) - 1 - piperazinyl) - N - pivaloyl sydnone imineand physiologically tolerable acid addition salts thereof beingcompounds of claim
 1. 7. 3-(4 - (2-pyrimidinyl) - 1 - piperazinyl) - N -(3,4,5, -trimethoxybenzoyl) sydnone imine and physiologically tolerableacid addition salts thereof being compounds of claim 1.